- Email: [email protected]
TRIGLYCERIDE METABOLISM IN THYROID DISEASE
391
TRIGLYCERIDE METABOLISM IN THYROID DISEASE B. LEWIS T. RUSSELL FRASER
B. R. TULLOCH
Endocrine Unit, and Department of Chemical Pathology, Royal Postgraduate Medical School, London W12 0HS
The fasting levels of plasma-triglycerSummary ide were increased in nine out of ten primary hypothyroid subjects, and they returned towards normal after thyroxine therapy. In seven thyrotoxic patients, fasting triglyceride levels were low normal and the mean levels did not change after antithyroid therapy. The clearance-rate of an infused triglyceride load showed abnormalities more striking than the changes observed in circulating triglyceride level. The clearance-rate in hypothyroid subjects was low and in the thyrotoxic patients it was either high or normal. After treatment of either state the fractional clearance-rates tended towards normal. There were parallel changes in free-fatty-acid flux. In the hypothyroid subjects, a slow clearance of exogenous triglyceride was associated with low postheparin lipolytic activity (P.H.L.A.), but in the thyrotoxic subjects the rapid clearance of triglyceride was associated with unexpected low or low normal P.H.L.A. levels. It is suggested that in thyroid disease the tissue clearance of circulating triglycerides may be an important determinant of fasting plasma-triglyceride values. Introduction
A RAISED level of circulating triglyceride is a risk factor for coronary disease1 and is a feature of hypothyroidism in most,2-4but not all, published reports.55 Bastenie et al.and Fowler et al.’ claimed that preclinical
myxoedema was not an uncommon finding in patients with hypercholesterolsemia and coronary vascular disease, but other workers disagree.8 In some cases of hyperlipideemia, thyroxine administration has been shown to reduce both fasting cholesterol and triglyceride levels.9,10 The thyroid analogue dextrothyroxine retained this lipid-lowering effect despite the addition of propranolol to block thyromimetic cardiovascular side-effects." Clofibrate may reduce triglyceride levels by displacing thyroxine from thyroxine-binding sites on the plasma-proteins. 12 Little information is available on the effect of excess thyroid hormone on circulating triglyceride metabolism. The increased circulating triglyceride in hypothyroid plasma is carried on the very low-density (V.L.D.L.) or pre-p-lipoprotein fraction 13 which is produced in the liver and splanchnic bed by esterification of circulating free fatty acids (F.F.A.).13,14 The hepatic production of triglycerides is not easily measured,15116 though the plasma-F.F.A. levels and turnover can be calculated using isotopic methods to give an index of the substrate available for hepatic triglyceride production. The rate of clearance of circulating triglycerides can be assessed by measuring the fractional clearance-rate of injected triglyceride. 17,18 Clearance of circulating triglycerides at the capillary wall is accomplished by the activity of the lipoprotein (clearing factor) lipase system. This enzyme system is active at the capillary endothelium and hydrolyses the triglyceride fraction of circulating chylomicrons and V.L.D.L., thus allowing transfer of the fatty-acid moiety across the capillary wall for metabolism or storage. 19 Changes in the activity of lipoprotein lipase could therefore alter the clearance-rate of plasma-triglyceride and hence affect circulating plasma levels. We have investigated triglyceride metabolism in ten hypothyroid and seven thyrotoxic subjects when they
TABLE I-CLINICAL DETAILS OF PATIENTS STUDIED
t. d. s. = Three times T3 =
a day. Triiodothyronine.
392
untreated and after appropriate therapy. We have measured the fasting triglyceride levels, the rate of clearance of an injected triglyceride load,1and also the post-heparin lipolytic activity (P.H.L.A.),13, 19 as well as the fasting F.F.A. levels and F.F.A. flux as an index of the F.F.A.-precursor pool available for hepatic
were
production
of
triglycerides. Methods
Ten
patients with primary myxoedema and
seven
thyrotoxic patients, as defined by standard clinical criteria (table i), were studied after obtaining their informed
consent. Where possible the test was repeated after restoration of normal thyroid function. After an overnight fast of 14 hours, a fine polyethylene catheter was inserted into each brachial vein and the patient kept in bed for the duration of the experiment. 25 µCi of C14-palmitate was complexed with sterile human albumin and infused at a constant rate over 90 minutes. Bloodsamples (10 ml.) were taken initially and after isotope equilibrium into iced heparin tubes for extraction and microtitration of F.F.A.20 21and determination of F.F.A. specific activity.22 From these data the F.F.A. flux per kg. body-weight was calculated using the formula:
R.
Sp. A. xW. R. =rate of infusion (d.p.m. per minute). Sp. A. =F.F.A. specific activity at equilibrium (d.p.m. W. =body-weight.
per
µeq.).
After this infusion, 01 g. per kg. of a triglyceride emulsion (’ Intralipid R’, Vitrum, batch 191249) was injected and timed blood-samples were taken into chilled edeticacid tubes over the subsequent 40 minutes for nephelometric estimation of injected triglyceride content. 18 Finally, 10 units per kg. heparin was injected as a pulse dose and plasma was collected after 10 minutes for estimation Of P.H.L.A.9 Results
Fasting levels of plasma-triglycerides (fig. 1).-In the untreated hypothyroid subject these levels were raised (9/10 subjects) and after thyroxine therapy they fell towards the normal range. In untreated thyrotoxi-
cosis, fasting plasma-triglyceride values were subnormal or low normal and after adequate therapy there was no significant change in the mean fasting triglyceride levels for the group. Fig. 1-Fasting plasma-triglycerides in myxoedematous and thyrotoxic patients before and after satisfactory treatment with thyroxine, carbimazole, or surgery as appropriate. Hatched areas =normal range. 2Mean difference for myxcedema was
was
-81-5 mg. (P<0°001). -5-1 mg. (p=O.73).
Mean difference for
thyrotoxicosis
2-Clearance of injected triglyceride in the fat-tolerance in a myxoedematous patient and a thyrotoxic patient before and after treatment.
Fig.
test
The fractional
(K,) was calculated 0-693 , 100% °
turnover-rate
T
as:
I - -y- ,0
where K2=exponential rate-constant in % per minute and the half-time of triglyceride clearance.
T½=
Fig. 3-Triglyceride-clearance rates in myxcedema and thyrotoxicosis before and after therapy. Mean difference for myxcedema was + 1-4 (P =0005), l2ear: difference for
thyrotoxicosis was - 5.6 (P=0.03).
393
Fig. 4-Interrelation between fasting plasma-triglycerides and fractional turnover-rates of injected triglyceride in the fattolerance test in patients with myxoedema or thyrotoxicosis. The arrows indicate the direction of change after treatment.
Fig. 5-Free-fatty-acid turnover before and after treatment for myxcedema or thyrotoxicosis. Mean difference for myxoedema was 29-8 µM per litre plasma Mean difference for thyrotoxicosis was per hour (P =0-014). 14-8 µM per litre
plasma
per hour
(P=0.07).
Clearance of infused triglyceride load (figs 2 and 3).In the ten untreated hypothyroid patients the clearance of infused triglyceride was low before treatment and rose towards normal after treatment with thyroxine. Similarly, the triglyceride-clearance rates in thyrotoxicosis were high or normal and the abnormal values returned towards normal after treatment of the
thyroxine administration to myxoœdematous patients. P.H.L.A. (table III) was reduced in myxœdema, returning to normal after thyroxine. Five thyrotoxic patients had a low or low normal P.H.L.A. and the values increased towards normal in four out of five patients
hyperthyroid
after
state.
Correlation between fasting triglyceride levels and clearance of exogenous triglyceride.-There was a more than tenfold rise in clearance-rate of an infused triglyceride load in patients with myxoedema as compared with thyrotoxic patients, and after appropriate treatment these values returned towards the normal range in both cases (fig. 4).
Fasting plasma-F.F.A. levels and flux.-In thyrotoxicosis the fasting plasma-F.F.A. flux was increased compared with the treated states (fig. 5). Myxcedematous patients, however, had a lower F.F.A. flux which increased after thyroxine administration. The F.F.A. TABLE II-PLASMA-F.F.A. IN PATIENTS WITH THYROID DISEASE
levels (table II) fell in thyrotoxicosis after treatment, but the converse was not
satisfactory seen
treatment.
Discussion
Our results confirm previous findings 2-4 that the circulating levels of triglyceride are raised in myxoedema, and low normal in cases of thyrotoxicosis. In myxoedema these levels returned towards normal on correction of the endocrine disorder. The triglyceride levels therefore change with thyroid function in a similar manner to cholesterol. The raised levels of triglyceride in myxoedema could well be one of the risk factors leading to the increased frequency of coronary heartdisease in the patients described by Bastenie et al. 6,10 The rise in fasting triglyceride levels could be caused either by decreased clearance, or by increased hepatic TABLE
III-P.H.L.A.IN
MYXŒDEMA AND THYROTOXICOSIS, AND
AFTER SATISFACTORY TREATMENT
*
Mean difference for myxoedema= 16-9 (p = 83). Mean difference for thyrotoxicosis= 134-9 (p = 0-018).
after
* Normal range = 28-52 uM glycerol/litre/hour.2. t Mean difference for myxœdema=29.8 (P= 0.0143). Mean difference for thyrotoxicosis 14 8 (p 0-0752). =
=
394 of V.L.D.L. from circulating F.F.A., or by both mechanisms. In so far as we may presume that the disposal of an infused triglyceride load reflects metabolism of the endogenous triglycerides (which are cleared from the circulation by the same mechanism), our results suggest that the clearance of endogenous triglyceride is reduced in myxcedema. The relation between fasting triglyceride values and the rate-constant of injected triglyceride removal (K2) differs significantly in thyroid disease from the pattern reported in alcoholic hypertriglyceridoemia, 2in which fivefold changes in fasting triglyceride level were observed without significant alteration in K2 values. This reciprocal relation between fasting triglyceride level and K values observed in thyroid disease is compatible with the view that the abnormal fasting triglyceride levels observed in myxoedema may result primarily from reduced clearance of triglyceride from the plasma. Furthermore, serum-P.H.L.A. is reduced in myxoedema and reverts towards normal after thyroxine therapy. The reduced P.H.L.A. in some cases of thyrotoxicosis, although unexpected, accords with the findings of Kirkleby.4 These workers demonstrated that thyroxine administration to rabbits mimicked the changes observed in man. In our studies the lower P.H.L.A. was nevertheless accompanied by rapid removal of circulating triglyceride load. We suggest, therefore, that excess thyroxine does not have a deleterious effect on the triglyceride-clearing system as postulated by Kirkleby, but perhaps has an effect on some aspect of lipoprotein-lipase release from the capillary wall after heparin injection, which would be reflected in lower measured P.H.L.A. values. Other possibilities, including the accelerated rate of capillary perfusion or increased catabohsm of the released lipoprotein lipase, have not been excluded in the present study. We have measured the F.F.A. levels and flux as an index of available F.F.A. for hepatic triglyceride production. Havel et al. 14,15 demonstrated that F.F.A. incorporation into circulating triglyceride fatty acids (T.G.F.A.) was proportional to the circulating F.F.A. levels. We found that the changes in F.F.A. flux after alteration in thyroid status would not lead to a situation in which increased liver production of triglyceride could explain the mechanism for the hypertriglyceridæmia seen in myxœdema. We conclude, therefore, that myxoedema is accompanied by an increase in fasting plasma-triglycerides which may be related to reduced clearance of lipid from the plasma. In thyrotoxicosis, low normal fasting triglyceride levels accompany the brisk removal of triglyceride. In neither condition do the changes in F.F.A. level or flux with treatment suggest hepatic synthesis as an important determinant of circulating triglyceride levels in the fasting state.
production
DETERIORATION IN RENAL FUNCTION IN ASSOCIATION WITH CO-TRIMOXAZOLE THERAPY STEVEN KALOWSKI TIMOTHY H. MATHEW
Department of Nephrology and University of Melbourne Department of Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia Deterioration in renal function has been observed in sixteen patients in association with co-trimoxazole treatment. This was reversible in most of them, but three patients showed permanent impairment of renal function. In five patients with impaired renal function in whom a modification of the standard dose regimen was used renal function further deteriorated. It is suggested that co-trimoxazole should not be used when the serumcreatinine is above 2 mg. per 100 ml.
Summary
Introduction was introduced in 1968, used and has widely proved very effective in infections.1-5 Adverse reactions, almost urinary-tract all of which have been non-renal, have been reported in as few as 0 4 %6 and in as many as 8 7 % 5 of patients treated. In 1969 Hanley 6 reported one case of crystalluria and one case of urinary retention and four cases of oliguria in association with the use of cotrimoxazole, but since that time there have been no published reports of nephrotoxicity. We describe here significant deterioration in renal
CO-TRIMOXAZOLE, which
has been
*
Present address: Royal Newcastle Wales, Australia.
Requests
for
reprints should be addressed
to
B. R. T.
Hospital, Newcastle,
New South
DR TULLOCH AND OTHERS: REFERENCES 1. 2. 3. 4.
5. 6. 7.
8. 9.
Carlson, L., Böttiger, L. E. Lancet, 1972, i, 865. Furman, R., Howard, R. W., Kappangula, L. Am. J. clin. Nutr. 1961, 9, 73. O’Hara, D., Porte, D. Metabolism, 1966, 15, 123. Kirkleby, K. Acta endocr., Copenh. 1968, 59, 55. Peters, J., Mann, E. B. J. clin. Invest. 1950, 29, 1. Bastenie, P. A., Vanhaelst, L., Bonnyns, M., Neve, P., Staquet, M. Lancet, 1971, i, 203. Fowler, P. B. S., Swale, J., Andrews, H. ibid. 1970, ii, 488. Heinonen, O. P., Gordin, A., Aho, K., Punsar, S., Pyorälä, K., Puro, K. ibid. 1972, i, 785. Eisalo, A., Ahrenberg, D., Nikkila, E. Acta med. scand. 1963, 173, 639.
Calay, R., Kocheleff, P., Jonniaux, G., Sohet, L., Bastenie, P. A. Lancet, 1971, i, 205. 11. Krikler, D. M., Lefevre, D., Lewis, B. ibid. p. 934. 12. Thorp, J., Cotton, R., Oliver, M. F. Progr. Biochem. Pharmac. 1968, 4, 611. 13. Fredriksen, D., Levy, R., Lees, R. New Engl. J. Med. 1967, 276, 32. 14. Havel, R. J. Metabolism, 1961, 10, 1031. 15. Havel, R. J., Kane, J., Balasse, E. D., Segel, M., Basso, L. J. clin. Invest. 1970, 49, 2017. 16. Boberg, J., Carlson, L., Freyshuss, U. Eur. J. clin. Invest. 1972, 2,
10.
123. 17.
We thank the M.R.C. for a project grant and for a clinical research fellowship (B. R. T.). We also thank our clinical colleagues, including Dr C. Lowy, Dr P. Read, and Dr N. Thalassinos, for referral of cases for study; Vitrum Laboratories and Paines and Byrne Ltd. for generous supplies of ’ Intralipid ’; and Miss Carmel Kelly, who kindly undertook P.H.L.A. measurements.
RANJIT SINGH NANRA* PRISCILLA KINCAID-SMITH
Boberg, J., Carlson,
L.
A., Hallberg, D. Atheroscler. Res. 1971, 9,
159.
Lewis, B., Boberg, J., Mancini, M., Carlson, L. A. Atherosclerosis, 1972, 15, 83. 19. Scow, R. O. Lipids, 1972, 7, 492. 20. Dole, V. P. J. clin. Invest. 1956, 35, 150. 21. Goss, J. E., Lein, A. Clin. Chem. 1967, 13, 36. 22. McCarthy, R., Duthie, A. J. Lipid Res. 1962, 3, 117. 23. Chait, A., Mancini, M., February, A. W., Lewis, B. Lancet, 1972, ii, 62. 24. Kelly, C. M.SC. thesis, University of Dublin, 1971. 25. Greenhalgh, R., Rowe, P. Unpublished. 18.
TRIGLYCERIDE METABOLISM IN THYROID DISEASE B. LEWIS T. RUSSELL FRASER
B. R. TULLOCH
Endocrine Unit, and Department of Chemical Pathology, Royal Postgraduate Medical School, London W12 0HS
The fasting levels of plasma-triglycerSummary ide were increased in nine out of ten primary hypothyroid subjects, and they returned towards normal after thyroxine therapy. In seven thyrotoxic patients, fasting triglyceride levels were low normal and the mean levels did not change after antithyroid therapy. The clearance-rate of an infused triglyceride load showed abnormalities more striking than the changes observed in circulating triglyceride level. The clearance-rate in hypothyroid subjects was low and in the thyrotoxic patients it was either high or normal. After treatment of either state the fractional clearance-rates tended towards normal. There were parallel changes in free-fatty-acid flux. In the hypothyroid subjects, a slow clearance of exogenous triglyceride was associated with low postheparin lipolytic activity (P.H.L.A.), but in the thyrotoxic subjects the rapid clearance of triglyceride was associated with unexpected low or low normal P.H.L.A. levels. It is suggested that in thyroid disease the tissue clearance of circulating triglycerides may be an important determinant of fasting plasma-triglyceride values. Introduction
A RAISED level of circulating triglyceride is a risk factor for coronary disease1 and is a feature of hypothyroidism in most,2-4but not all, published reports.55 Bastenie et al.and Fowler et al.’ claimed that preclinical
myxoedema was not an uncommon finding in patients with hypercholesterolsemia and coronary vascular disease, but other workers disagree.8 In some cases of hyperlipideemia, thyroxine administration has been shown to reduce both fasting cholesterol and triglyceride levels.9,10 The thyroid analogue dextrothyroxine retained this lipid-lowering effect despite the addition of propranolol to block thyromimetic cardiovascular side-effects." Clofibrate may reduce triglyceride levels by displacing thyroxine from thyroxine-binding sites on the plasma-proteins. 12 Little information is available on the effect of excess thyroid hormone on circulating triglyceride metabolism. The increased circulating triglyceride in hypothyroid plasma is carried on the very low-density (V.L.D.L.) or pre-p-lipoprotein fraction 13 which is produced in the liver and splanchnic bed by esterification of circulating free fatty acids (F.F.A.).13,14 The hepatic production of triglycerides is not easily measured,15116 though the plasma-F.F.A. levels and turnover can be calculated using isotopic methods to give an index of the substrate available for hepatic triglyceride production. The rate of clearance of circulating triglycerides can be assessed by measuring the fractional clearance-rate of injected triglyceride. 17,18 Clearance of circulating triglycerides at the capillary wall is accomplished by the activity of the lipoprotein (clearing factor) lipase system. This enzyme system is active at the capillary endothelium and hydrolyses the triglyceride fraction of circulating chylomicrons and V.L.D.L., thus allowing transfer of the fatty-acid moiety across the capillary wall for metabolism or storage. 19 Changes in the activity of lipoprotein lipase could therefore alter the clearance-rate of plasma-triglyceride and hence affect circulating plasma levels. We have investigated triglyceride metabolism in ten hypothyroid and seven thyrotoxic subjects when they
TABLE I-CLINICAL DETAILS OF PATIENTS STUDIED
t. d. s. = Three times T3 =
a day. Triiodothyronine.
392
untreated and after appropriate therapy. We have measured the fasting triglyceride levels, the rate of clearance of an injected triglyceride load,1and also the post-heparin lipolytic activity (P.H.L.A.),13, 19 as well as the fasting F.F.A. levels and F.F.A. flux as an index of the F.F.A.-precursor pool available for hepatic
were
production
of
triglycerides. Methods
Ten
patients with primary myxoedema and
seven
thyrotoxic patients, as defined by standard clinical criteria (table i), were studied after obtaining their informed
consent. Where possible the test was repeated after restoration of normal thyroid function. After an overnight fast of 14 hours, a fine polyethylene catheter was inserted into each brachial vein and the patient kept in bed for the duration of the experiment. 25 µCi of C14-palmitate was complexed with sterile human albumin and infused at a constant rate over 90 minutes. Bloodsamples (10 ml.) were taken initially and after isotope equilibrium into iced heparin tubes for extraction and microtitration of F.F.A.20 21and determination of F.F.A. specific activity.22 From these data the F.F.A. flux per kg. body-weight was calculated using the formula:
R.
Sp. A. xW. R. =rate of infusion (d.p.m. per minute). Sp. A. =F.F.A. specific activity at equilibrium (d.p.m. W. =body-weight.
per
µeq.).
After this infusion, 01 g. per kg. of a triglyceride emulsion (’ Intralipid R’, Vitrum, batch 191249) was injected and timed blood-samples were taken into chilled edeticacid tubes over the subsequent 40 minutes for nephelometric estimation of injected triglyceride content. 18 Finally, 10 units per kg. heparin was injected as a pulse dose and plasma was collected after 10 minutes for estimation Of P.H.L.A.9 Results
Fasting levels of plasma-triglycerides (fig. 1).-In the untreated hypothyroid subject these levels were raised (9/10 subjects) and after thyroxine therapy they fell towards the normal range. In untreated thyrotoxi-
cosis, fasting plasma-triglyceride values were subnormal or low normal and after adequate therapy there was no significant change in the mean fasting triglyceride levels for the group. Fig. 1-Fasting plasma-triglycerides in myxoedematous and thyrotoxic patients before and after satisfactory treatment with thyroxine, carbimazole, or surgery as appropriate. Hatched areas =normal range. 2Mean difference for myxcedema was
was
-81-5 mg. (P<0°001). -5-1 mg. (p=O.73).
Mean difference for
thyrotoxicosis
2-Clearance of injected triglyceride in the fat-tolerance in a myxoedematous patient and a thyrotoxic patient before and after treatment.
Fig.
test
The fractional
(K,) was calculated 0-693 , 100% °
turnover-rate
T
as:
I - -y- ,0
where K2=exponential rate-constant in % per minute and the half-time of triglyceride clearance.
T½=
Fig. 3-Triglyceride-clearance rates in myxcedema and thyrotoxicosis before and after therapy. Mean difference for myxcedema was + 1-4 (P =0005), l2ear: difference for
thyrotoxicosis was - 5.6 (P=0.03).
393
Fig. 4-Interrelation between fasting plasma-triglycerides and fractional turnover-rates of injected triglyceride in the fattolerance test in patients with myxoedema or thyrotoxicosis. The arrows indicate the direction of change after treatment.
Fig. 5-Free-fatty-acid turnover before and after treatment for myxcedema or thyrotoxicosis. Mean difference for myxoedema was 29-8 µM per litre plasma Mean difference for thyrotoxicosis was per hour (P =0-014). 14-8 µM per litre
plasma
per hour
(P=0.07).
Clearance of infused triglyceride load (figs 2 and 3).In the ten untreated hypothyroid patients the clearance of infused triglyceride was low before treatment and rose towards normal after treatment with thyroxine. Similarly, the triglyceride-clearance rates in thyrotoxicosis were high or normal and the abnormal values returned towards normal after treatment of the
thyroxine administration to myxoœdematous patients. P.H.L.A. (table III) was reduced in myxœdema, returning to normal after thyroxine. Five thyrotoxic patients had a low or low normal P.H.L.A. and the values increased towards normal in four out of five patients
hyperthyroid
after
state.
Correlation between fasting triglyceride levels and clearance of exogenous triglyceride.-There was a more than tenfold rise in clearance-rate of an infused triglyceride load in patients with myxoedema as compared with thyrotoxic patients, and after appropriate treatment these values returned towards the normal range in both cases (fig. 4).
Fasting plasma-F.F.A. levels and flux.-In thyrotoxicosis the fasting plasma-F.F.A. flux was increased compared with the treated states (fig. 5). Myxcedematous patients, however, had a lower F.F.A. flux which increased after thyroxine administration. The F.F.A. TABLE II-PLASMA-F.F.A. IN PATIENTS WITH THYROID DISEASE
levels (table II) fell in thyrotoxicosis after treatment, but the converse was not
satisfactory seen
treatment.
Discussion
Our results confirm previous findings 2-4 that the circulating levels of triglyceride are raised in myxoedema, and low normal in cases of thyrotoxicosis. In myxoedema these levels returned towards normal on correction of the endocrine disorder. The triglyceride levels therefore change with thyroid function in a similar manner to cholesterol. The raised levels of triglyceride in myxoedema could well be one of the risk factors leading to the increased frequency of coronary heartdisease in the patients described by Bastenie et al. 6,10 The rise in fasting triglyceride levels could be caused either by decreased clearance, or by increased hepatic TABLE
III-P.H.L.A.IN
MYXŒDEMA AND THYROTOXICOSIS, AND
AFTER SATISFACTORY TREATMENT
*
Mean difference for myxoedema= 16-9 (p = 83). Mean difference for thyrotoxicosis= 134-9 (p = 0-018).
after
* Normal range = 28-52 uM glycerol/litre/hour.2. t Mean difference for myxœdema=29.8 (P= 0.0143). Mean difference for thyrotoxicosis 14 8 (p 0-0752). =
=
394 of V.L.D.L. from circulating F.F.A., or by both mechanisms. In so far as we may presume that the disposal of an infused triglyceride load reflects metabolism of the endogenous triglycerides (which are cleared from the circulation by the same mechanism), our results suggest that the clearance of endogenous triglyceride is reduced in myxcedema. The relation between fasting triglyceride values and the rate-constant of injected triglyceride removal (K2) differs significantly in thyroid disease from the pattern reported in alcoholic hypertriglyceridoemia, 2in which fivefold changes in fasting triglyceride level were observed without significant alteration in K2 values. This reciprocal relation between fasting triglyceride level and K values observed in thyroid disease is compatible with the view that the abnormal fasting triglyceride levels observed in myxoedema may result primarily from reduced clearance of triglyceride from the plasma. Furthermore, serum-P.H.L.A. is reduced in myxoedema and reverts towards normal after thyroxine therapy. The reduced P.H.L.A. in some cases of thyrotoxicosis, although unexpected, accords with the findings of Kirkleby.4 These workers demonstrated that thyroxine administration to rabbits mimicked the changes observed in man. In our studies the lower P.H.L.A. was nevertheless accompanied by rapid removal of circulating triglyceride load. We suggest, therefore, that excess thyroxine does not have a deleterious effect on the triglyceride-clearing system as postulated by Kirkleby, but perhaps has an effect on some aspect of lipoprotein-lipase release from the capillary wall after heparin injection, which would be reflected in lower measured P.H.L.A. values. Other possibilities, including the accelerated rate of capillary perfusion or increased catabohsm of the released lipoprotein lipase, have not been excluded in the present study. We have measured the F.F.A. levels and flux as an index of available F.F.A. for hepatic triglyceride production. Havel et al. 14,15 demonstrated that F.F.A. incorporation into circulating triglyceride fatty acids (T.G.F.A.) was proportional to the circulating F.F.A. levels. We found that the changes in F.F.A. flux after alteration in thyroid status would not lead to a situation in which increased liver production of triglyceride could explain the mechanism for the hypertriglyceridæmia seen in myxœdema. We conclude, therefore, that myxoedema is accompanied by an increase in fasting plasma-triglycerides which may be related to reduced clearance of lipid from the plasma. In thyrotoxicosis, low normal fasting triglyceride levels accompany the brisk removal of triglyceride. In neither condition do the changes in F.F.A. level or flux with treatment suggest hepatic synthesis as an important determinant of circulating triglyceride levels in the fasting state.
production
DETERIORATION IN RENAL FUNCTION IN ASSOCIATION WITH CO-TRIMOXAZOLE THERAPY STEVEN KALOWSKI TIMOTHY H. MATHEW
Department of Nephrology and University of Melbourne Department of Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia Deterioration in renal function has been observed in sixteen patients in association with co-trimoxazole treatment. This was reversible in most of them, but three patients showed permanent impairment of renal function. In five patients with impaired renal function in whom a modification of the standard dose regimen was used renal function further deteriorated. It is suggested that co-trimoxazole should not be used when the serumcreatinine is above 2 mg. per 100 ml.
Summary
Introduction was introduced in 1968, used and has widely proved very effective in infections.1-5 Adverse reactions, almost urinary-tract all of which have been non-renal, have been reported in as few as 0 4 %6 and in as many as 8 7 % 5 of patients treated. In 1969 Hanley 6 reported one case of crystalluria and one case of urinary retention and four cases of oliguria in association with the use of cotrimoxazole, but since that time there have been no published reports of nephrotoxicity. We describe here significant deterioration in renal
CO-TRIMOXAZOLE, which
has been
*
Present address: Royal Newcastle Wales, Australia.
Requests
for
reprints should be addressed
to
B. R. T.
Hospital, Newcastle,
New South
DR TULLOCH AND OTHERS: REFERENCES 1. 2. 3. 4.
5. 6. 7.
8. 9.
Carlson, L., Böttiger, L. E. Lancet, 1972, i, 865. Furman, R., Howard, R. W., Kappangula, L. Am. J. clin. Nutr. 1961, 9, 73. O’Hara, D., Porte, D. Metabolism, 1966, 15, 123. Kirkleby, K. Acta endocr., Copenh. 1968, 59, 55. Peters, J., Mann, E. B. J. clin. Invest. 1950, 29, 1. Bastenie, P. A., Vanhaelst, L., Bonnyns, M., Neve, P., Staquet, M. Lancet, 1971, i, 203. Fowler, P. B. S., Swale, J., Andrews, H. ibid. 1970, ii, 488. Heinonen, O. P., Gordin, A., Aho, K., Punsar, S., Pyorälä, K., Puro, K. ibid. 1972, i, 785. Eisalo, A., Ahrenberg, D., Nikkila, E. Acta med. scand. 1963, 173, 639.
Calay, R., Kocheleff, P., Jonniaux, G., Sohet, L., Bastenie, P. A. Lancet, 1971, i, 205. 11. Krikler, D. M., Lefevre, D., Lewis, B. ibid. p. 934. 12. Thorp, J., Cotton, R., Oliver, M. F. Progr. Biochem. Pharmac. 1968, 4, 611. 13. Fredriksen, D., Levy, R., Lees, R. New Engl. J. Med. 1967, 276, 32. 14. Havel, R. J. Metabolism, 1961, 10, 1031. 15. Havel, R. J., Kane, J., Balasse, E. D., Segel, M., Basso, L. J. clin. Invest. 1970, 49, 2017. 16. Boberg, J., Carlson, L., Freyshuss, U. Eur. J. clin. Invest. 1972, 2,
10.
123. 17.
We thank the M.R.C. for a project grant and for a clinical research fellowship (B. R. T.). We also thank our clinical colleagues, including Dr C. Lowy, Dr P. Read, and Dr N. Thalassinos, for referral of cases for study; Vitrum Laboratories and Paines and Byrne Ltd. for generous supplies of ’ Intralipid ’; and Miss Carmel Kelly, who kindly undertook P.H.L.A. measurements.
RANJIT SINGH NANRA* PRISCILLA KINCAID-SMITH
Boberg, J., Carlson,
L.
A., Hallberg, D. Atheroscler. Res. 1971, 9,
159.
Lewis, B., Boberg, J., Mancini, M., Carlson, L. A. Atherosclerosis, 1972, 15, 83. 19. Scow, R. O. Lipids, 1972, 7, 492. 20. Dole, V. P. J. clin. Invest. 1956, 35, 150. 21. Goss, J. E., Lein, A. Clin. Chem. 1967, 13, 36. 22. McCarthy, R., Duthie, A. J. Lipid Res. 1962, 3, 117. 23. Chait, A., Mancini, M., February, A. W., Lewis, B. Lancet, 1972, ii, 62. 24. Kelly, C. M.SC. thesis, University of Dublin, 1971. 25. Greenhalgh, R., Rowe, P. Unpublished. 18.